This Funding Opportunity Announcement (FOA) solicits Research Project Grant (R01) applications addressing exceptionally novel hypotheses and/or remarkably difficult problems in neuroscience and disorders of the nervous system. This announcement is for support of new rather than ongoing projects, and is not intended for pilot research. The proposed research may have a high risk of failure, but it must promise results with especially high impact should it be successful. The research should be groundbreaking, innovative, original and/or unconventional, with the potential to solve important problems or open new areas for investigation.